The neurological basis of pain and the neural circuits that underlie pain perception and pain inhibition remain fundamental problems for neuroscientists. Much research in the past 25 years has focused on mechanisms in the brain that modulate pain sensitivity, especially those mechanisms related to the neurotransmitters and neuromodulators that control pain. This application addresses the possibility that endogenous ligands for the cannabinoid receptor play a significant role within neural circuits that modulate of pain sensitivity. The molecular basis for this hypothesis is the discovery and cloning of a G-protein coupled cannabinoid receptor and the identification of a putative endogenous ligand called anandamide. Because drugs of this class produce powerful inhibition of pain responses in animals, the possibility arises that the endogenous counterpart play a role in the neuronal mechanisms of pain inhibition. By delineating the functional role of cannabinoids, a better understanding of the neural basis of pain and pain inhibition would be achieved. The proposed experiments address the possibility that endogenous cannabinoid may play a role in the neurological basis of pain by examining the effects of cannbinoids on neural systems that are involved in pain processing. To assess these actions on pain pathways in the brain, an examination of the effects of cannabinoids on pain-evoked expression of c- fos like immunoreactivity i spinal cord is proposed. In a parallel line of research, an examination of the effects of cannabinoids on the firing of neurons in the thalamus and spinal cord is proposed. These experiments provide a means to build a theoretical model of the actions of endogenous cannabinoids within specific brain circuits that modify pain transmission. The studies may have clinical significance because they may provide a basis for estimating the efficacy of cannabinoids as a pharmacotherapy for pain.